The invention relates to a novel process for preparing specific 1-substituted 5-hydroxy-imidazoline-2,4-diones starting from N-substituted urea and glyoxylic acid and the further conversion of these 1-substituted 5-hydroxy-imidazoline-2,4-diones into 1-substituted 5-alkoxy-imidazoline-2,4-diones.
1-Benzyl-5-ethoxy-imidazoline-2,4-dione of the formula (A) 
(hereinafter referred to as xe2x80x9cBEHxe2x80x9d) belongs to the class of hydantoins and is also referred to as 1-benzyl-5-ethoxyhydantoin. BEH, its derivatives which are substituted on the benzyl ring and also other 1-substituted 5-alkoxy-imidazoline-2,4-diones have gained increasing importance as intermediates in the preparation of medicaments, insecticides, textile assistants and amino acids. BEH itself is required, in particular, for the preparation of photochemicals.
It is known from Huaxue Shiji 1993, 15(1), 15-16, that BEH can be prepared from the corresponding 1-benzylhydantoin by bromination or chlorination in the 5 position to give the corresponding 1-benzyl-5-halogenohydantoins and further reaction of these halogenohydantoins with ethanol (see reaction equation below). 
The above reaction sequence has a number of disadvantages: thus, the use of free bromine or chlorine is difficult in terms of industrial handling and is not without danger. Furthermore, large amounts of hydrogen halides are obtained in the halogenation itself and also in the subsequent halogen replacement, and these have to be disposed of.
The starting material for the abovementioned chlorination or bromination, namely 1-benzylhydantoin, also referred to as 1-benzyl-imidazoline-2,4-dione, in turn has to be prepared via a number of steps:
a) by reaction of N-benzylaminoacetonitrile (a product of the addition of benzylamine and hydrocyanic acid onto formaldehyde) and cyanic acid (JP 06 100 543 A2) or
b) by reaction of N-benzylglycine (or its derivatives) and urea or cyanic acid (Huaxue Shiji 1993 15(1), 15-16).
The starting material for the abovementioned synthetic route a), viz. N-benzyl-aminoacetonitrile, is prepared by reaction of benzylamine and formaldehyde with the extremely toxic hydrocyanic acid (see also Tetrahedron Letters [23], 27 (1982), 2741-4). The starting material for the synthetic route b), viz. N-benzylglycine, also firstly has to be prepared by reaction of glycine with benzyl chloride or of chloroacetic acid with benzylamine. The reaction of N-benzylaminoacetonitrile or N-benzylglycine as per a) or b) is carried out either by fusion with urea for a long time or by reaction with the toxic cyanic acid. Both methods give 1-benzyl-hydantoin in only low yields: thus, according to Huaxue Shiji 1993, 15(1) 15-16, the reaction of N-benzylglycine (obtained by reaction of benzylarnine with chloroacetic acid) with cyanic acid gives 1-benzylhydantoin in a yield of only 39.5% and the reaction of N-benzylglycine with urea gives 1-benzylhydantoin in a yield of only 45.6%. The subsequent bromination of the 1-benzylhydantoin and treatment with ethanol again proceeds in only a low yield of 42.7%.
Furthermore, Huaxue Shiji 1993 15(1), 15-16 merely states that glyoxylic acid can in principle be used as starting material for a reaction with a substituted urea. However, no information is given regarding the reaction conditions which have to be adhered to to carry out such a reaction successfully.
In addition, it is known from JP 09 227 526 A2 that N-substituted ureas of the formula RNxe2x80x3HCONH2, where Rxe2x80x3=alkyl or aryl, can be reacted with alkyl glyoxylate alkyl hemiacetals of the formula ROCH(OH)COORxe2x80x2, where R, Rxe2x80x2=alkyl, in a solvent or a solvent mixture. This firstly forms, apart from a large number of other compounds, the corresponding 1-alkyl- or 1-aryl-substituted 5-hydroxy-hydantoin of the formula (B). 
In the case of Rxe2x80x3=benzyl, the reaction thus forms 1-benzyl-5-hydroxyhydantoin of the formula (C) 
in addition to many other compounds. The multicomponent reaction mixture, which contains, inter alia, the 1-alkyl- or 1-aryl-substituted 5-hydroxy-hydantoin, is obtained as a viscous, oily mass and is virtually impossible to purify. Before the further reaction, it has to be carefully dewatered and subsequently reacted with an alcohol and mineral acid by prolonged heating, which again forms, owing to the impure composition of the reaction mixture used, a mixture of a number of compounds, including the desired 1-alkyl- or 1-aryl-5-alkoxy-imidazoline-2,4-dione.
The isolation of the desired 1-alkyl- or 1-aryl-5-alkoxy-imidazoline-2,4-dione is therefore complicated and has to be carried out by column chromatography. This separation has been described only on the gram scale, is hardly feasible in industry and gives the desired product in a yield of only 44% and in unknown purity (JP 09 227 526 A2, Example 1).
In addition, the starting compounds for this synthesis, i.e. the alkyl glyoxylate alkyl hemiacetals, firstly have to be synthesized by independent routes. They are obtained as mixtures of hemiacetals and acetals and likewise have to be purified in a costly manner.
EP-A-0 160 618 describes the reaction of glyoxylic esters or o-alkylglyoxylic esters (glyoxylic ester alkoxides) with N-alkylureas, N-cycloalkylureas, N,Nxe2x80x2-dialkylureas or N,Nxe2x80x2-dicycloalkylureas in a solvent such as water and/or acetic acid. In addition, it is established that this reaction can also be carried out using glyoxylic acid itself. In Example 2 of EP-A-0 160 618, the reaction of glyoxylic acid with N-methylurea is carried out in an aqueous acetic acid solution. The product obtained is said to be 5-hydroxy-3-methylhydantoin, but no information is given on the yield or selectivity of the reaction. Repeating the in-principle reaction of glyoxylic acid with N-methylurea gave only small amounts of a greasy crystalline product which represents a very complicated mixture of many substances and whose separation by crystallization is not practical. NMR analysis of this crystalline product indicated, alongside many other compounds in small amounts, the two isomeric 1- and 3-methyl-5-hydroxyhydantoins in approximately equal amounts of about 10%. In view of the lack of a yield figure in Example 2 of EP-A-0 160 618, it therefore has to be assumed that only small amounts of 1-methyl-5-hydroxy-hydantoin were isolated there. The process of EP-A-0 160 618 using alkyl- or cycloalkyl-substituted ureas can therefore not be regarded as a suitable possible method of preparing 1-alkyl-5-hydroxy-hydantoins.
Tetrahedron 33 (1977), pp. 1191-1196, discloses the reaction of glyoxylic acid with N-methylurea. However, without use of a catalyst, this reaction in methanol gives 5-methoxy-3-methylhydantoin.
Since the demand for 1-substituted 5-alkoxy-imidazoline-2,4-diones is continually increasing in view of the many possible applications mentioned above, it is an object of the present invention to provide a process by means of which the 1-substituted 5-hydroxy-imidazoline-2,4-diones required as intermediates for the synthesis of the 1-substituted 5-alkoxy-imidazoline-2,4-diones can be prepared in high yield and high purity using simple-to-handle and nontoxic chemicals. In particular, the process to be provided should make complicated purification of the 1-substituted 5-hydroxy-imidazoline-2,4-diones, e.g. by column chromatography, superfluous.
These and other features, aspects, and advantages of the present invention will become better understood with reference to the following description and appended claim.
This object is achieved by a process for preparing 1-substituted 5-hydroxy-imidazoline-2,4-diones of the formula (I) 
where R represents a substituted or unsubstituted C6-C12-aryl radical or a substituted or unsubstituted C7-C18-aralkyl radical, by reacting glyoxylic acid with an N-substituted urea of the formula RNHxe2x80x94COxe2x80x94NH2, where R is as defined above, characterized in that the process is carried out in a 10-80% strength aqueous solution in the presence of an acid catalyst.
Surprisingly, the reaction of glyoxylic acid and the N-substituted urea in aqueous solution and in the presence of the acid catalyst can be carried out successfully and in a controlled manner. It is essential that the reaction is carried out in aqueous solution. This results in the glyoxylic acid being predominantly present in the form of the hydrate.
The process of the invention displays a high selectivity to the 1-substituted 5-hydroxy-imidazoline-2,4-dione, which is at least 60%, mostly at least 70% and often even 75% or more. Apart from the 1-substituted 5-hydroxy-imidazoline-2,4-dione, the by-products which are possible according to the following reaction equation are formed in only very small amounts. 
The N-substituted ureas used in the process of the invention have the formula RNHxe2x80x94COxe2x80x94NH2, where R represents a substituted or unsubstituted C6-C12-aryl radical or a substituted or unsubstituted C7-C18-aralkyl radical. The aryl radicals may be substituted by 1, 2, 3, 4 or 5 identical or different radicals selected from the group consisting of halogen, preferably chlorine, C1-C12-alkyl, preferably methyl, NO2, C1-C12-alkoxy, preferably methoxy, and phenoxy.
Preference is given to using N-substituted ureas of the formula RNHxe2x80x94COxe2x80x94NH2, where R represents a substituted or unsubstituted C6-C10-aryl radical or a substituted or unsubstituted C7-C12-aralkyl radical. R particularly preferably represents a benzyl radical or a benzyl radical substituted by 1, 2, 3, 4 or 5 of the abovementioned radicals, for example 3,4-dimethoxybenzyl, 4-methylbenzyl or 4-chlorobenzyl. Further suitable aralkyl radicals are 3-phenylpropyl, 1-phenylethyl and 2-phenylethyl. A suitable substituted aryl radical is 4-chlorophenyl.
The process of the invention is carried out in the presence of an acid catalyst. Acetic acid has been found to be particularly useful as catalyst. It is also possible to use catalysts whose pKa values are similar to that of acetic acid. These include potassium or sodium dihydrogenphosphates or potassium or sodium hydrogenphosphates. It is likewise possible to use other acid catalysts such as, for example, formic acid, propionic acid, boric acid, phosphoric acid, oxalic acid or alkali metal hydrogensulphates.
The molar ratio of glyoxylic acid to the N-substituted urea is (0.5-2):1, preferably (0.8-1.2):1. Particular preference is given to using equimolar or virtually equimolar) amounts of glyoxylic acid and N-substituted urea. In one embodiment, the molar ratio of glyoxylic acid to the N-substituted urea is (0.5-5):1, and preferably (0.8-2):1.
It is an essential aspect of the process of the invention that it is carried out in a 10-80% strength, preferably 20-70% strength and in particular 40-60% strength, aqueous solution. The glyoxylic acid can accordingly be used, for example, in the form of its approximately 50% strength aqueous solution.
In addition, other organic solvents such as hydrocarbons, alcohols or esters may also be present in the process of the invention.
The process of the invention is usually carried out at a temperature in the range 80-120xc2x0, preferably 95-105xc2x0 C. At reaction temperatures close to the boiling point of the reaction mixture (about 100xc2x0 C.), the reaction between glyoxylic acid and the N-substituted urea is rapid and complete. To achieve residual contents of N-substituted urea of less than 1%, it has been found to be useful to stir the reaction mixture for 1-2 hours after the actual reaction.
The process of the invention has been found to be particularly useful for preparing 1-benzyl-5-hydroxy-imidazoline-2,4-dione by reacting benzylurea with glyoxylic acid in aqueous solution in the presence of an acid catalyst, in particular acetic acid. The isolation of the desired product, namely the 1-substituted 5-hydroxy-imidazoline-2,4-dione of the formula (I), is usually achieved by crystallization which can be carried out either with or without additional addition of solvent. An additional solvent is preferably added to the crystallization mixture, since the crystallization then forms a crystalline product of higher purity which can be filtered off very readily. Suitable solvents are, in general, aliphatic hydrocarbons such as hexane, heptane or isooctane, halogenated hydrocarbons such as methylene chloride, substituted or unsubstituted aromatic hydrocarbons such as benzene, toluene, ethylbenzene and chlorinated benzenes or toluenes, ketones such as acetone or methyl ethyl ketone or ethers such as methyl tert-butyl ether or methyl isopropyl ether. The addition of methylene chloride or chlorobenzene has been found to be particularly useful. The crystallization temperature is preferably below 40xc2x0 C. If no additional solvents are used in the crystallization, the product firstly crystallizes together with a relatively small amount of impurities. In this case in particular, it has been found useful to purify the desired product, viz. the 1-substituted 5-hydroxy-imidazoline-2,4-dione, in a simple manner by recrystallization. If the 5-benzylurea-1-benzyl-imidazoline-2,4-dione content is too high, crystallization from hot water has been found to be very advantageous. The solubility of this by-product in hot water is low, so that it can be filtered off from the hot solution of the desired 1-substituted 5-hydroxy-imidazoline-2,4-dione.
Further drying of the 1-substituted 5-hydroxy-imidazoline-2,4-dione before it is reacted further is not absolutely necessary. However, it has been found that the chemical losses in the further reaction to the 1-substituted 5-alkoxy-imidazoline-2,4-dione can be minimized if the 1-substituted 5-hydroxy-imidazoline-2,4-dione contains as little water as possible. It can therefore be dried, if desired, by simple air or vacuum drying at room temperature or elevated temperature or else by azeotropic distillation of water with the aid of suitable entrainers.
The reaction product of the reaction between glyoxylic acid and the N-substituted urea, in particular the preferred 1-benzyl-5-hydroxy-imidazoline-2,4-dione, does not, however, necessarily have to be isolated as an intermediate. It is also possible to remove the major part of the solvent from the crude reaction mixture by distillation and to react the oily product further in this form without additional treatment. It is also possible to separate the crude product as an oily lower phase by cooling the crude reaction mixture.
In a further embodiment of the process of the invention, the 1-substituted 5-hydroxy-imidazoline-2,4-diones of the formula I which have been prepared are reacted in a further step to form 1-substituted 5-alkoxy-imidazoline-2,4-diones of the formula II 
where R is as defined for the formula I and R1 represents a straight-chain or branched C1-C18-alkyl radical, preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, octyl or 2-ethylhexyl and in particular ethyl.
The conversion of the 1-substituted 5-hydroxy-imidazoline-2,4-diones of the formula I into the 1-substituted 5-alkoxy-imidazoline-2,4-diones of the formula II can be carried out in various ways. Suitable methods are, for example:
1) reaction of the 1-substituted 5-hydroxy-imidazoline-2,4-dione of the formula I with an alcohol of the formula R1OH in the presence of an acid catalyst.
Such an acid-catalyzed etherification is described, for example, in JP 09 227 526 A2. The alcohol used is preferably ethanol. The 1-substituted 5-hydroxy-imidazoline-2,4-dione, which has preferably been dried to form a solid and is, in particular, virtually water-free, is reacted with the alcohol. It has been found to be useful to use at least 1 mol of alcohol per mole of 1-substituted 5-hydroxy-imidazoline-2,4-dione. The acid catalyst used is preferably a protic acid. This protic acid has, in particular, a negative pKa. Such protic acids are described in xe2x80x9cAdvanced Organic Chemistryxe2x80x9d (editor: J. March, John Wiley and Sons 1985, 3rd edition, chapter 8). Examples are hydrochloric acid (pKa=xe2x88x927), hydrobromic acid (pKa=xe2x88x929), sulphuric acid (pKa=xe2x88x929) and organic sulphonic acids (pKa=xe2x88x926.5). Preferred examples of organic sulphonic acids include methanesulphonic acid, trifluoromethanesulphonic acid, benzenesulphonic acid and p-toluenesulphonic acid. The acid is used in an amount of 0.001-10 mol, preferably 0.01-1 mol and in particular 0.01-0.03 mol, per mole of 1-substituted 5-hydroxy-imidazoline-2,4-dione. The reaction temperature is 0-120xc2x0 C., preferably 20-100xc2x0 C. The reaction time is usually 4-20 hours.
2) Reaction of the 1-substituted 5-hydroxy-imidazoline-2,4-dione of the formula I with a tri-C1-C18-alkyl orthoformate, in particular triethyl orthoformate.
This reaction is likewise acid-catalysed and proceeds very quickly. The reaction temperature is in the range 20-160xc2x0 C., preferably 50-130xc2x0 C. and particularly preferably 70-120xc2x0 C. The reaction time is usually 1-10 hours. As catalysts, it is possible to use all acids which have been mentioned above for variant 1). The molar ratio of the trialkyl orthoformate to the 1-substituted 5-hydroxy-imidazoline-2,4-dione is usually (0.5-5):1. Particular preference is given to using equimolar amounts of trialkyl orthoformate and 1-substituted 5-hydroxy-imidazoline-2,4-dione.
3) Reaction of the 1-substituted 5-hydroxy-imidazoline-2,4-dione of the formula I firstly with thionyl chloride and subsequently with an alcohol R1OH, where R1 is as defined above.
The reaction temperature is in the range 50-150xc2x0 C., preferably 60-100xc2x0 C. The reaction time is 1-20 hours. The molar ratio of thionyl chloride to the 1-substituted 5-hydroxy-imidazoline-2,4-dione is (0.5-5):1. This reaction can be carried out in the presence or absence of an organic solvent. Suitable solvents are aliphatic, chlorinated or aromatic hydrocarbons, preferably benzene or toluene.
The 1-substituted 5-alkoxy-imidazoline-2,4-dione is preferably isolated by crystallization from its alcoholic solutions, since this is the operation which is easiest to carry out in industry.
It is also possible to prepare the product as a melt and to allow this to crystallize by cooling or to carry out the solvent crystallization from other solvents instead of ethanol.
Further complicated purification steps are not necessary, since the 1-substituted 5-alkoxy-imidazoline-2,4-dione obtained by all three routes 1), 2) and 3) has a significantly higher purity than comparable 1-substituted 5-alkoxy-imidazoline-2,4-diones prepared by the reaction sequences of the prior art. This is a result of the excellent selectivity of the process of the invention to the intermediate, namely the 1-substituted 5-hydroxy-imidazoline-2,4-dione.
The invention is further described in the following illustrative examples in which all parts and percentages are by weight unless otherwise indicated.